Recent developments in the treatment of inflammatory bowel disease

Invited review

Recent developments in the treatment of inflammatorybowel disease

Svend T. RIETDIJK & Geert R. D’HAENS

Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam,Amsterdam, The Netherlands

Crohn’s disease and ulcerative colitis are chronicinflammatory bowel diseases that have been treatedwith corticosteroids, 5-aminosalicates and thiopu-rines, but therapeutic options have been broadenedwith the arrival of anti-tumor necrosis factor anti-bodies. In this article we reviewed the current evidence-based approach to inflammatory bowel disease, themodifications that have been made to existing thera-

pies and discussed new drugs that have shown successin clinical trials. The new drugs discussed here are thosethat disturb lymphocyte homing to the gut (natali-zumab, vedolizumab and anti-mucosal addressin cel-lular adhesion molecule); one that blocks interleukin(IL)-12 as well as the IL-23/T helper 17 (Th17) axis(ustekinumab) and one that blocks the signaling ofmultiple cytokines (tofacitinib).

KEY WORDS: Crohn’s disease, inflammatory bowel disease, natalizumab, tofacitinib, ulcerative colitis,ustekinumab.

INTRODUCTION

Crohn’s disease (CD) and ulcerative colitis (UC) aredistinct disease entities that are grouped under theterm inflammatory bowel disease (IBD) because oftheir common immunological pathophysiology. IBDis most frequently diagnosed in the second or thirddecade of life and patients typically present withchronic abdominal pain and altered bowel habits.Often there is a delay in diagnosis because abdominalpain and other symptoms can mimic the irritablebowel syndrome (IBS) and gastrointestinal infection.The similarity between CD and UC has in the past

resulted in parallel treatments, often with success. Themainstay of remission induction has been based onvarious formulations of corticosteroids while mainte-nance therapy has typically relied on 5-aminosalicates(5-ASA) and thiopurines. Anti-tumor necrosis factor(TNF) antibodies are effective for both the inductionand maintenance of remission and are usuallyreserved for those more severe and/or steroid-dependent patients.

In this article we addressed three principal issues toillustrate current developments: first of all, the currentevidence-based approach to CD and UC; second, themodifications that have been made to existing thera-pies; and third, the therapies targeting new pathwaysthat have been tested.

THE CURRENT EVIDENCE-BASED APPROACH TOCD AND UC

For decades the initial medical treatment forIBD has consisted of corticosteroids, typically(methyl)prednisolone or hydrocortisone. While

Correspondence to: Geert R. D’HAENS, Department of Gastroenterologyand Hepatology, Academic Medical Center, University of Amsterdam,P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. Email:[email protected]

Conflict of interest: None.

© 2013 The AuthorsJournal of Digestive Diseases © 2013 Wiley Publishing Asia PtyLtd and Chinese Medical Association Shanghai Branch, ChineseSociety of Gastroenterology, Renji Hospital Affiliated to ShanghaiJiaotong University School of Medicine

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Journal of Digestive Diseases 2013; 14; 282–287 doi: 10.1111/1751-2980.12048

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corticosteroids are excellent at inducing remission,maintenance therapy is problematic because thedisease may become refractory and many side effectsdevelop. 5-ASA-based therapies are very effective atinducing and maintaining remission in UC but arerarely recommended for CD due to limited evidenceof their efficacy.1

The introduction of anti-TNF antibodies has been aturning point. Infliximab was the first anti-TNF anti-body made available and was proved to be effective inthe induction and maintenance of IBD remission, aswell as in the treatment of fistulizing disease in thecase of CD.2 Adalimumab, a subcutaneous humananti-TNF antibody, is also effective for the treatment ofCD and UC.2–4

We typically treat mild to moderate UC first with oraland/or topical 5-ASA preparations. Oral and/ortopical corticosteroid preparations (budesonide orbeclomethasone) are added if symptoms persist.5

Once remission has been reached, preferably judgedby the normalization of calprotectin or documentedby endoscopy, we taper off the admission of steroidsand use 5-ASA as maintenance therapy. Unless there isisolated distal disease (proctitis), we try to maintainremission with oral, slow-release 5-ASA preparations.Even in cases of repeated exacerbations, we try to opti-mize oral and topical 5-ASA therapy (often in combi-nation) to control the disease. If multiple inductioncourses or steroids are needed, however, the introduc-tion of thiopurine maintenance therapy is recom-mended.5,6 Since thiopurines are slow-acting agents,the first few months of treatment are usually com-bined with steroids in tapering schedules. In cases ofsevere UC we use high-dose oral prednisolone. Ifsymptoms persist, however, we rapidly step up thetreatment by admitting the patients to the hospital fori.v. prednisolone. If improvement is not evident after 3days, we consider infliximab or cyclosporine.5

In CD, remission is preferably induced withbudesonide. More severe disease presentations,for example, with extraintestinal manifestations,however, require systemic steroid treatment with(methyl)prednisolone.7 Once remission has beenreached, many patients receive maintenance treatmentwith azathioprine/6-mercaptopurine.8 In a substantialgroup of moderate to severe cases, however, this doesnot offer sufficient disease control. If patients haverepeated flares, we introduce infliximab or adali-mumab to induce and maintain remission, withongoing concomitant immunosuppressive treatment.

In both UC and CD we rarely discontinue 5-ASA,thiopurines or anti-TNF therapy after successful induc-tion of remission, although the financial burden ofbiological therapy is considerable, and its long-termcost-effectiveness has not been firmly established forUC.

One of the most important aspects of managing IBDis accurate disease-monitoring and record-keepingthroughout the patient’s life. This helps to establishthe course the disease is taking, the medicationsthat have been tried and the result of the treatmentadministered.

MODIFICATIONS THAT HAVE RECENTLY BEENMADE TO EXISTING THERAPIES

Novel delivery mode of 5-ASA: multi-matrix(MMX) mesalazine

Traditional oral 5-ASA preparations are not very effec-tive in distal UC, probably because sufficient mucosalconcentrations are not reached in the rectum.9 This isthe reason why rectal formulations can be combinedwith oral therapy to ensure more effective treatment ofleft-sided UC.10 However, slow release of the activeingredient constitutes a more elegant and patient-friendly option. It has also been shown that splitdosing of oral 5-ASA can be replaced by once dailyadministration.11

A new MMX delivery system of 1.2 g of MMX mesala-zine was tested in a preliminary trial in UC andshowed similar rates of remission induction to thecombination of mesalazine enema and oral placeboin patients with left-sided colitis.12 In two pivotal trialswith MMX mesalazine at higher doses13,14 patientswith active UC were randomized to receive 2.4 g or4.8 g of MMX mesalazine once daily versus placebo or800 mg of slow-release mesalazine. Endoscopic andclinical remission rates were superior with MMXmesalazine.

Novel delivery of topical steroids: budesonideMMX

With the emergence of delayed release budesonide,including Entocort (AstraZeneca, Sodertalje, Sweden)and Budenofalk (Dr. Falk Pharma GmbH, Freiberg,Germany), topical corticosteroid therapy of the termi-nal ileum and colon has become possible. BudesonideMMX (Cosmo Pharmaceuticals, Lainate, Italy) is aonce daily oral formulation of budesonide using a

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© 2013 The AuthorsJournal of Digestive Diseases © 2013 Wiley Publishing Asia Pty Ltd and Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology,Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine

MMX technology to extend the release of budesonidethroughout the colon.15 A randomized pilot studyshowed that budesonide MMX was safe and effectivein treating left-sided colitis,16 which was subsequentlyconfirmed in a randomized, double-blind, double-dummy, placebo-controlled trial in which two dosesof budesonide MMX were compared with placebo andmesalazine.17 The results showed that 9 mg budes-onide MMX led to higher rates of clinical and endo-scopic remission than the placebo. This drug iscurrently undergoing regulatory review.

Altering the intestinal microbiome: rifaximin

Gut bacteria play a crucial role in the developmentand maintenance of IBD. Hence, changing the micro-biome is an attractive approach in developing noveltherapies. Usually, antibiotics are not recommendedfor the treatment of inflammation in CD or UC, apartfrom fistulizing disease, septic complications or pou-chitis. While certain trials have shown a beneficialeffect, the use of different antibiotics in small groupsof patients have made evidence-based recommenda-tions difficult.1 It is also unclear whether the antibioticeffect is due to the removal of specific detrimentalbacteria, or to a new balance in the gut flora.

Rifaximin is a broad spectrum antibiotic that exerts itsbactericidal effect mainly in the gut lumen, as it isnot absorbed. Following a promising open-label trialin CD,18 two placebo-controlled trials were per-formed with a delayed release preparation (rifaximin-extended intestinal release (EIR). Prantera et al.randomized 83 patients with active CD to 800 mg ofrifaximin-EIR once or twice daily or placebo. Whencompared to placebo they demonstrated that the twicedaily dose was more effective in inducing a responsebut the differences in remission rates were not statis-tically significant.19 Some of the investigators went onto enroll 402 patients in a trial with three doses ofrifaximin-EIR or placebo and showed that a dose of800 mg twice daily induced remission with fewadverse events in patients with moderately active CDover a 12-week period. The authors noted, however,that there was a lack of a dose–response relationshipand a higher than expected placebo response.20

Rifaximin was also tested in UC in a randomized,double-blind trial in 26 patients.21 Although there wasno statistically significant difference in clinical activitybetween the two groups, rifaximin resulted in symp-tomatic and endoscopic improvement comparedto the placebo-treated group. We should, however,

remain cautious of long-term antibiotic therapybecause of the possibility of antibiotic resistance.

New ways of targeting TNF: certolizumab pegoland golimumab

While anti-TNF therapy can hardly be considered new,it is worth mentioning that there have been advancesin the types of antibodies that have and will becomeavailable. Since the arrival of infliximab, changes havebeen made in the way TNF is targeted. Infliximab is amouse–human chimeric antibody and adalimumab isa fully human antibody. Both are large proteins thatcan elicit antibodies and bind Fc receptors on variouscells. The development of antibodies against thesepreparations reduces efficacy and causes adverseevents.

In an attempt to reduce immunogenicity and increasethe serum half-life, a pegylated form of an anti-TNFFab′ fragment was constructed and named certoli-zumab pegol.

Several trials have shown that certolizumab pegol iseffective in the induction and maintenance of remis-sion in patients with CD, especially those with raisedC-reactive protein and a short history of disease.22–26 Ameta-analysis showed a particular benefit with certoli-zumab pegol in the maintainance of remission.2 Addi-tional data indicated that patients who previouslyresponded to infliximab, but who have lost theresponse or became intolerant, are likely to respond tocertolizumab.27

An even more recent anti-TNF antibody is golimumab,another fully human molecule that is s.c. adminis-tered. Golimumab has so far only been tested in mod-erate to severe UC, showing favorable effect oninduction and the maintenance of remission as well ason mucosal healing.28

NEW PATHWAYS BEING TARGETED IN IBD

Inhibition of leukocyte homing: natalizumab,vedolizumab and anti-mucosal addressin cellularadhesion molecule (anti-MAdCAM)

Natalizumab is a recombinant humanized antibodythat was derived from a murine monoclonal antibodyoriginally raised against human a4 integrin. a4 inte-grin is expressed on certain lymphocytes and, as partof a dimer with other integrin chains such as b7 or b1,binds ligands on endothelium, such as MAdCAM and

Journal of Digestive Diseases 2013; 14; 282–287284 ST Rietdijk and GR D’Haens

© 2013 The AuthorsJournal of Digestive Diseases © 2013 Wiley Publishing Asia Pty Ltd and Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology,

Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine

vascular cellular adhesion molecule 1 (VCAM-1). Therationale behind natalizumab therapy is that by block-ing the a4 molecule in particular, certain lymphocytesare prevented from homing to the gut and entering theintestinal tissues. This strategy has proven successful inmultiple randomized placebo-controlled trials inpatients with CD29–32 and was also effective in multiplesclerosis (MS).33–35 There are, however, significantsafety concerns after reports of patients who deve-loped progressive multifocal leukoencephalopathy(PML) due to reactivation of JC virus.36 The reason forthis phenomenon was that a4 blockade reduced lym-phocyte homing not only to the gut but also to thecentral nervous system. Natalizumab is now availableonly in North America without concomitant immuno-suppression and with a strict monitoring programincluding JC virus serology. Until recently, this moni-toring program has identified 212 confirmed cases ofPML in 99 571 MS patients (0.213%) who hadreceived natalizumab for more than a month.37

Vedolizumab is an antibody directed against both thea4 and b7 integrins when they are in complex, whichimplies high specificity for gut-homing lymphocytes,thereby avoiding effects on the immunity of centralnervous system. An initial trial by Feagan et al.38 in2005 showed the efficacy of this antibody in inducinga short-term response and remission in patients withactive UC.

In 2012 a large phase III trial showed impressiveresults for the induction and maintenance of remis-sion, steroid withdrawal and mucosal healing in UC,including in patients who had previously failed anti-TNF treatment.39 Vedolizumab was also tested in CDand although the primary end point (clinical responseat day 57, defined as a 70-point or higher decrementin CD activity index [CDAI] score from baseline) wasnot met, there seemed to be a dose-dependent effect,mainly beyond week 6.40 Reports from a recentlycompleted phase III trial have supported these find-ings as significantly more patients with moderate tosevere CD achieved and stayed in remission whentreated with 4-weekly or 8-weekly infusion ofvedolizumab.41,42 The safety data of the studiesrevealed a very reassuring profile. In particular, therewas no increased incidence of infection, adding addi-tional proof to the selective intestinal mechanism ofaction of this drug. It is likely that vedolizumab willbecome commercially available in the coming years.

The antibody PF-00547,659 provides an alternativeway of blocking the a4b7 interaction with the

endothelium by binding and blocking endothelialMAdCAM. This was tested in a preliminary trial toassess its safety and efficacy in UC.43 While the resultswere not significant, they were very favorable andfurther trials are underway in both UC and CD.

Blocking of interleukin (IL-12) signaling andthe IL-23/Th17 axis: ustekinumab

Ustekinumab is a monoclonal antibody generated inhuman immunoglobulin G (IgG) transgenic miceimmunized with IL-12. IL-12 has a p40 subunit whichshares with IL-23. Ustekinumab was tested in a phaseIIa trial in CD and although the primary end point wasnot met, significant differences with placebo werefound in patients who had previously received inflix-imab.44 This was an important finding because manypatients treated with anti-TNF agents lose response orbecome intolerant over time. To address this in moredetail, an additional trial was performed in patientswho were resistant to anti-TNF treatment.45 Here, sig-nificant differences in response rate were found and ifthe patients did respond initially they were more likelyto reach remission when on maintenance therapy.

Ustekinumab probably acts by neutralizing theinflammatory effects of IL-12 and IL-23, thereby dis-rupting the development and/or function of T helper 1(Th1) and Th17 cells, which are known to play animportant role in the development of CD.46 The drugis already widely available for the treatment of psoria-sis and is likely to become available for refractory CDin the years ahead.

Blocking multiple cytokine signaling: tofacitinib(CP-690550)

Tofacitinib is a selective oral inhibitor of the Januskinase (JAK) family of kinases that mediates signaltransduction activity involving the common gammachain of the receptors for multiple cytokines. Thisagent was shown to inhibit a number of innate andadaptive immune responses including the activationand differentiation of T cells and the innate responseto lipopolysaccharides.47 In addition, clinical trials inrheumatoid arthritis were successful,48–50 leading tothe approval of the drug by Food and Drugs Admin-istration (FDA) of USA for this indication. In an8-week phase II trial of patients with moderately orseverely active UC, treatment using tofacitinib resultedin significant improvements in clinical and endo-scopic response and remission.51 The drug is currentlybeing investigated in phase III programs.



FUTURE CONSIDERATIONS

We have reviewed therapies that have demonstratedeffects in controlled trials but many more interestingtherapies are currently being tested.52 Due to thediscovery of susceptibility genes, novel cell subsetsand insights into antigen-processing and cell signal-ing we will have a much better understanding of thebasis of CD and UC. With the arrival of targetedtherapy in the form of monoclonal antibodies,RNA-antisense, small molecule inhibitors and RNA-interference-based therapy, we have been given toolsto manipulate specific processes. By integrating thesetechnologies and the expanding number of candidatepathways, a number of new medications can beexpected to reach the market in the coming years.This requires a better understanding of biologicalmechanisms, drug kinetics and potential side effects.We have found that close collaboration between clini-cal and research laboratories, other specialisms suchas rheumatology, and pharmaceutical companieshave been of paramount importance in creatingprogress in this expanding field.

REFERENCES

1 Talley NJ, Abreu MT, Achkar JP et al; American College ofGastroenterology IBD Task Force. An evidence-basedsystematic review on medical therapies for inflammatorybowel disease. Am J Gastroenterol 2011; 106 Suppl 1: S2–25;quiz S26.

2 Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ,Moayyedi P. Efficacy of biological therapies in inflammatorybowel disease: systematic review and meta-analysis. Am JGastroenterol 2011; 106: 644–59, quiz 660.

3 Sandborn WJ, van Assche G, Reinisch W et al. Adalimumabinduces and maintains clinical remission in patients withmoderate-to-severe ulcerative colitis. Gastroenterology 2012;142: 257–65. e3.

4 Sandborn WJ, Colombel JF, D’Haens G et al. One-yearmaintenance outcomes among patients withmoderately-to-severely active ulcerative colitis whoresponded to induction therapy with adalimumab:subgroup analyses from ULTRA 2. Aliment Pharmacol Ther2013; 37: 204–13.

5 Dignass A, Lindsay JO, Sturm A et al. Second Europeanevidence-based consensus on the diagnosis andmanagement of ulcerative colitis part 2: currentmanagement. J Crohns Colitis 2012; 6: 991–1030.

6 Timmer A, McDonald JW, Tsoulis DJ, Macdonald JK.Azathioprine and 6-mercaptopurine for maintenance ofremission in ulcerative colitis. Cochrane Database Syst Rev2012; 9: CD000478.

7 Dignass A, Van Assche G, Lindsay JO et al; EuropeanCrohn’s and Colitis Organisation (ECCO). The secondEuropean evidence-based Consensus on the diagnosis andmanagement of Crohn’s disease: Current management.J Crohns Colitis 2010; 4: 28–62.

8 Prefontaine E, Sutherland LR, Macdonald JK, Cepoiu M.Azathioprine or 6-mercaptopurine for maintenance ofremission in Crohn’s disease. Cochrane Database Syst Rev2009; (1): CD000067.

9 Frieri G, Pimpo MT, Palumbo GC et al. Rectal and colonicmesalazine concentration in ulcerative colitis: oral vs. oralplus topical treatment. Aliment Pharmacol Ther 1999; 13:1413–7.

10 Marteau P, Probert CS, Lindgren S et al. Combined oral andenema treatment with Pentasa (mesalazine) is superior tooral therapy alone in patients with extensive mild/moderateactive ulcerative colitis: a randomised, double blind, placebocontrolled study. Gut 2005; 54: 960–5.

11 Tong JL, Huang ML, Xu XT, Qiao YQ, Ran ZH. Once-dailyversus multiple-daily mesalamine for patients with ulcerativecolitis: a meta-analysis. J Dig Dis 2012; 13: 200–7.

12 Prantera C, Viscido A, Biancone L, Francavilla A, Giglio L,Campieri M. A new oral delivery system for 5-ASA:preliminary clinical findings for MMx. Inflamm Bowel Dis2005; 11: 421–7.

13 Lichtenstein GR, Kamm MA, Boddu P et al. Effect of once-or twice-daily MMX mesalamine (SPD476) for theinduction of remission of mild to moderately activeulcerative colitis. Clin Gastroenterol Hepatol 2007; 5: 95–102.

14 Kamm MA, Sandborn WJ, Gassull M et al. Once-daily,high-concentration MMX mesalamine in active ulcerativecolitis. Gastroenterology 2007; 132: 66–75; quiz 432–3.

15 Brunner M, Ziegler S, Di Stefano AF et al. Gastrointestinaltransit, release and plasma pharmacokinetics of a new oralbudesonide formulation. Br J Clin Pharmacol 2006; 61:31–8.

16 D’Haens GR, Kovács A, Vergauwe P et al. Clinical trial:Preliminary efficacy and safety study of a newBudesonide-MMX® 9 mg extended-release tablets in patientswith active left-sided ulcerative colitis. J Crohns Colitis 2010;4: 153–60.

17 Sandborn WJ, Travis S, Moro L et al. Once-daily budeso-nide MMX® extended-release tablets induce remission inpatients with mild to moderate ulcerative colitis: resultsfrom the CORE I study. Gastroenterology 2012; 143: 1218–26.e2.

18 Shafran I, Johnson LK. An open-label evaluation ofrifaximin in the treatment of active Crohn’s disease. CurrMed Res Opin 2005; 21: 1165–9.

19 Prantera C, Lochs H, Campieri M et al. Antibiotic treatmentof Crohn’s disease: results of a multicentre, double blind,randomized, placebo-controlled trial with rifaximin. AlimentPharmacol Ther 2006; 23: 1117–25.

20 Prantera C, Lochs H, Grimaldi M, Danese S, Scribano ML,Gionchetti P; Retic Study Group (Rifaximin-Eir Treatment inCrohn’s Disease). Rifaximin-extended intestinal releaseinduces remission in patients with moderately activeCrohn’s disease. Gastroenterology 2012; 142: 473–81.e4.

21 Gionchetti P, Rizzello F, Ferrieri A et al. Rifaximin inpatients with moderate or severe ulcerative colitis refractoryto steroid-treatment: a double-blind, placebo-controlledtrial. Dig Dis Sci 1999; 44: 1220–1.

22 Sandborn WJ, Schreiber S, Hanauer SB, Colombel JF, Bloom-field R, Lichtenstein GR; PRECiSE 4 Study Investigators. Rein-duction with certolizumab pegol in patients with relapsedCrohn’s disease: results from the PRECiSE 4 study. Clin Gas-troenterol Hepatol 2010; 8: 696–702.

23 Lichtenstein GR, Thomsen OØ, Schreiber S et al.Continuous therapy with certolizumab pegol maintainsremission of patients with Crohn’s disease for up to 18months. Clin Gastroenterol Hepatol 2010; 8: 600–9.

Journal of Digestive Diseases 2013; 14; 282–287286 ST Rietdijk and GR D’Haens

© 2013 The AuthorsJournal of Digestive Diseases © 2013 Wiley Publishing Asia Pty Ltd and Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology,

Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine

24 Sandborn WJ, Feagan BG, Stoinov S et al; PRECISE 1 StudyInvestigators. Certolizumab pegol for the treatment ofCrohn’s disease. N Engl J Med 2007; 357: 228–38.

25 Schreiber S, Khaliq-Kareemi M, Lawrance IC et al; PRECISE2 Study Investigators. Maintenance therapy withcertolizumab pegol for Crohn’s disease. N Engl J Med 2007;357: 239–50.

26 Schreiber S, Rutgeerts P, Fedorak RN et al; CDP870 Crohn’sDisease Study Group. A randomized, placebo-controlledtrial of certolizumab pegol (CDP870) for treatment ofCrohn’s disease. Gastroenterology 2005; 129: 807–18.

27 Sandborn WJ, Abreu MT, D’Haens G et al. Certolizumabpegol in patients with moderate to severe Crohn’s diseaseand secondary failure to infliximab. Clin GastroenterolHepatol 2010; 8: 688–95.

28 Sandborn WJ, Feagan BG, Marano CW et al. A phase 2/3randomized, placebo-controlled, double-blind study toevaluate the safety and efficacy of subcutaneous golimumabinduction therapy in patients with moderately to severelyactive ulcerative colitis: PURSUIT SC. Gastroenterology 2012;142: 161.

29 Targan SR, Feagan BG, Fedorak RN et al; InternationalEfficacy of Natalizumab in Crohn’s Disease Response andRemission (ENCORE) Trial Group. Natalizumab for thetreatment of active Crohn’s disease: results of the ENCORETrial. Gastroenterology 2007; 132: 1672–83.

30 Sandborn WJ, Colombel JF, Enns R et al; InternationalEfficacy of Natalizumab as Active Crohn’s Therapy(ENACT-1) Trial Group; Evaluation of Natalizumab asContinuous Therapy (ENACT-2) Trial Group. Natalizumabinduction and maintenance therapy for Crohn’s disease.N Engl J Med 2005; 353: 1912–25.

31 Ghosh S, Goldin E, Gordon FH et al; NatalizumabPan-European Study Group. Natalizumab for active Crohn’sdisease. N Engl J Med 2003; 348: 24–32.

32 Gordon FH, Lai CW, Hamilton MI et al. A randomizedplacebo-controlled trial of a humanized monoclonalantibody to a4 integrin in active Crohn’s disease.Gastroenterology 2001; 121: 268–74.

33 Rudick RA, Stuart WH, Calabresi PA et al; SENTINELInvestigators. Natalizumab plus interferon beta-1a forrelapsing multiple sclerosis. N Engl J Med 2006; 354:911–23.

34 Polman CH, O’Connor PW, Havrdova E et al; AFFIRMInvestigators. A randomized, placebo-controlled trial ofnatalizumab for relapsing multiple sclerosis. N Engl J Med2006; 354: 899–910.

35 Miller DH, Khan OA, Sheremata WA et al; InternationalNatalizumab Multiple Sclerosis Trial Group. A controlledtrial of natalizumab for relapsing multiple sclerosis. N Engl JMed 2003; 348: 15–23.

36 Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocalleukoencephalopathy complicating treatment withnatalizumab and interferon beta-1a for multiple sclerosis.N Engl J Med 2005; 353: 369–74.

37 Bloomgren G, Richman S, Hotermans C et al. Risk ofnatalizumab-associated progressive multifocal leukoence-phalopathy. N Engl J Med 2012; 366: 1870–80.

38 Feagan BG, Greenberg GR, Wild G et al. Treatment ofulcerative colitis with a humanized antibody to the a4b7

integrin. N Engl J Med 2005; 352: 2499–507.39 Feagan BG, Rutgeerts PJ, Sands BE et al. Induction therapy

for ulcerative colitis: results of GEMINI I, a randomized,placebo-controlled, double-blind, multicenter phase 3 trial.Gastroenterology 2012; 142: S160–1.

40 Feagan BG, Greenberg GR, Wild G et al. Treatment of activeCrohn’s disease with MLN0002, a humanized antibody tothe a4b7 integrin. Clin Gastroenterol Hepatol 2008; 6:1370–7.

41 Colombel J. Vedolizumab induction therapy for Crohn’sdisease: results of GEMINI II, a randomized, placebo-controlled, double-blind, multicenter phase 3 trial. UEGW2012 oral presentation 20–24 October 2012. Amsterdam,The Netherlands.

42 Colombel J. Vedolizumab maintenance therapy for Crohn’sdisease: results of GEMINI II, a randomized, placebo-controlled, double-blind, multicenter phase 3 trial. UEGW2012 oral presentation. 20–24 October 2012. Amsterdam,The Netherlands.

43 Vermeire S, Ghosh S, Panes J et al. The mucosal addressincell adhesion molecule antibody PF-00547,659 in ulcerativecolitis: a randomised study. Gut 2011; 60: 1068–75.

44 Sandborn WJ, Feagan BG, Fedorak RN et al; UstekinumabCrohn’s Disease Study Group. A randomized trial ofustekinumab, a human interleukin-12/23 monoclonalantibody, in patients with moderate-to-severe Crohn’sdisease. Gastroenterology 2008; 135: 1130–41.

45 Sandborn WJ, Gasink C, Gao LL et al; CERTIFI Study Group.Ustekinumab induction and maintenance therapy inrefractory Crohn’s disease. N Engl J Med 2012; 367:1519–28.

46 Elliott M, Benson J, Blank M et al. Ustekinumab: lessonslearned from targeting interleukin-12/23p40 in immune-mediated diseases. Ann N Y Acad Sci 2009; 1182: 97–110.

47 Ghoreschi K, Jesson MI, Li X et al. Modulation of innateand adaptive immune responses by tofacitinib(CP-690,550). J Immunol 2011; 186: 4234–43.

48 Kremer JM, Cohen S, Wilkinson BE et al. A phase IIbdose-ranging study of the oral JAK inhibitor tofacitinib(CP-690,550) versus placebo in combination withbackground methotrexate in patients with active rheumatoidarthritis and an inadequate response to methotrexate alone.Arthritis Rheum 2012; 64: 970–81.

49 Fleischmann R, Kremer J, Cush J et al.; ORAL SoloInvestigators. Placebo-controlled trial of tofacitinibmonotherapy in rheumatoid arthritis. N Engl J Med 2012;367: 495–507.

50 van Vollenhoven RF, Fleischmann R, Cohen S et al; ORALStandard Investigators. Tofacitinib or adalimumab versusplacebo in rheumatoid arthritis. N Engl J Med 2012; 367:508–19.

51 Sandborn WJ, Ghosh S, Panes J et al. Tofacitinib, an oralJanus kinase inhibitor, in active ulcerative colitis. N Engl JMed 2012; 367: 616–24.

52 Danese S. New therapies for inflammatory bowel disease:from the bench to the bedside. Gut 2012; 61: 918–32.



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Recent developments in the treatment of inflammatory bowel disease